CN1492861A - Process for preparation of citalopram - Google Patents
Process for preparation of citalopram Download PDFInfo
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- CN1492861A CN1492861A CNA028054199A CN02805419A CN1492861A CN 1492861 A CN1492861 A CN 1492861A CN A028054199 A CNA028054199 A CN A028054199A CN 02805419 A CN02805419 A CN 02805419A CN 1492861 A CN1492861 A CN 1492861A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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Abstract
This invention discloses an improved process for the preparation of citalopram of the formula (III) which comprises: (i) preparing the compound of the formula (VIII) by reducing an unisolable magnesium salt of a benzophenone derivative of the formula (V) using sodium borohydride in the presence of a protic solvent; (ii) reacting the compound of the formula (VIII) obtained in step (i) with an acid catalyst in a non-polar solvent to obtain a compound of the formula (I); (iii) reacting the compound of the formula (I) obtained in step (ii) with copper cyanide in a polar solvent medium and isolating the resulting cyano compound, by recrystallization by using polar and/or alcoholic solvents to obtain the compound of the formula (II); and (iv) reacting the resulting compound of the formula (II) by conventional methods to form citalopram of the formula (III). Citalopram is widely used as an antidepressant.
Description
The present invention relates to a kind of improving one's methods of citalopram that prepare.As everyone knows, citalopram is a kind of good thymoleptic of widespread use.The present invention also relates to the improving one's methods of intermediate of preparation formula I and II representative, these intermediates are to preparing a kind of well-known antidepressant drug citalopram of great use.
The compound of formula I and II representative is synthetic known thymoleptic 1-(3-dimethylamino-propyl)-1-(4 '-fluorophenyl)-1, the key intermediate of 3-dihydroisobenzofuran-5-acetonitrile (citalopram) (shown in formula III) and pharmaceutically-acceptable acid addition thereof.
Prepare the method for antidepressant drug citalopram and pharmaceutical properties thereof at first at DE patent No.2, open in 657,013 (1977), corresponding to US patent No.4,136,193 (1979), next also at GB patent No.1, open in 526,331 (1978).
The basic skills of the preparation citalopram of describing in the above-mentioned patent that relates to comprises two main routes, shown in scheme 1 and scheme 2, so the main difference point of these two lines is being introduced the dimethylamino-propyl side chain in last stage (scheme 1) or latter stage (scheme 2).
In article one route, the 5-bromobenzene shown in the formula IV also [C] furanone and bromination obtains the benzophenone derivates shown in the formula V to the fluorophenyl reactive magnesium.This benzophenone derivates and chlorination 3-N, N-dimethylamino-propyl reactive magnesium obtains the dihydroxyl intermediate shown in the formula VI.Carry out the cyclisation result with acid catalyst and form the phthalane derivative shown in the formula VII, this bromo phthalane derivative and cuprous cyanide reaction obtain the citalopram alkali shown in the formula III.
Scheme-1
In the second route, the 5-bromobenzene shown in the formula IV also [C] furanone and bromination obtains the benzophenone derivates shown in the formula V to the fluorophenyl reactive magnesium.This compound is obtained the dihydroxy compound shown in the formula VIII with lithium aluminium hydride reduction, this compound is obtained the phthalane derivative shown in the formula I with the acid catalyst cyclisation, replace the bromo base with cyano group, and carry out alkylation with needed side chain and can obtain citalopram alkali.
Scheme-2
Bogeso (EP patent No.171,943, corresponding to US patent No.4,650,884) show that the method for preparing citalopram in being used to described in the above-mentioned patent is carrying out there are some difficult problems when mass commercial is produced.
At the more short-circuit line of making great efforts a preparation of research citalopram and avoid in the previously used adventurous metallization step, it is starting raw material that Bogeso uses suc as formula the cyano group of the 5-shown in the IX-2-benzo [C] furanone, and be surprised to find, under 80 ℃, when carrying out cyclisation with 70% sulfuric acid, cyano group kept (square case 3).
Scheme-3
In international patent application no is WO98/019511, WO98/019512, and WO98/019513, WO99/030548, WO00/011926 in the international monopoly of WO00/013648 and WO00/023431, discloses further preparation method.Application number is to disclose the method for preparing citalopram in the international monopoly of WO98/019511, wherein the compound of formula X is reduced the compound that obtains formula XII with sodium borohydride, yet yield has only 40%, and has used a large amount of ethanol (～50 times).The compound of formula XII is carried out closed loop, and resulting 5-substituted-dihydro isobenzofuran derivative further is converted into corresponding 5-cyano derivative and carries out alkylation and obtain citalopram with 3-dimethylamino halogenopropane.
The described method of WO98/019512 and WO98/019513 is with 5-amino, 5-carboxyl or 5-secondary amino group carbonyl-2-benzo [C] furanone carries out two step successive grignard reactions, Guan Huan, and with 1 of gained, 3-dihydroisobenzofuran derivative is converted into corresponding 5-cyano derivative, just citalopram.
In the method for the western general phthalein orchid of international monopoly 99/030548 disclosed preparation, cyano group is introduced from the corresponding 5-aldehyde radical of citalopram analogue.
Among international monopoly WO 00/011926 and the WO 00/0133648 disclosed improved citalopram preparation method, the 5-halo of citalopram (Cl or Br) analogue is to introduce corresponding cyano group westwards in the general phthalein orchid by the activation of palladium or nickel complex catalyst.
In international monopoly WO 00/023431 disclosed method, the introducing of cyano group is finished via corresponding citalopram 5-oxazolyl analogue in the citalopram.
Is the impurity in the citalopram will be removed to reach the acceptable level of drug quality according to the method for original patent (at US patent No.4,136,193 in open) to the big shortcoming that citalopram carries out the mass-producing commercial production.Improve the citalopram method for quality or by chemical purification method (by the salt of the sour addition that can supply), or by molecular distillation.As if impurity can not removed acceptable level with chemical process, because some of them impurity has identical and the salifiable character of acid suc as formula the compound shown in VI, VII, the XIII.
In original patent, be used to prepare all intermediates that citalopram relates to all have very high boiling point (～200 ℃,＜0.1mmHg) and to overheated very sensitive.This also is the big shortcoming with this method commercialization the time.
The second route that in original patent, is used to prepare citalopram comprise with molecular distillation (180-200 ℃,＜0.1mmHg) midbody compound with formula I and II carries out purifying, also there is the difficulty of practice in this method when commercially producing.And this route also will use costliness and dangerous reagent, lithium aluminum hydride.
Article three, the route (at EP patent No.171,943 in open) of the simplification of preparation citalopram relate to introduce from the beginning citalopram with 5-cyano group.Also there is the big shortcoming of removing impurity in the product in this route.When the citalopram of the pharmaceutically acceptable quality of preparation, describe the technology of repeated recrystallization, but will obtain the product of needs, used this technology to have considerable damage.
Other international monopoly of all that deliver in the period of 1998 to 2000 comprises various methods from the different introducing 5-of functional group cyano group, and all these methods all concentrate on new chemical means, do not commercially produce but all be suitable for.
Citalopram has become a kind of well-known thymoleptic, and has put on market.It demonstrates huge prospect as the few and useful thymoleptic of a kind of toxic side effect.Consider the difficulty that the method commercialization for preparing citalopram above-mentioned is faced, we are devoted to study a kind of simple and economic method citalopram are commercially produced.
We notice, find such method, and approach likely is: the quality that (a) improves one or more separable intermediates with simple technology; (b) avoid using and resemble the so expensive dangerous again reagent of lithium aluminum hydride; (c) reduce waste water such as a large amount of phosphoric acid.
In view of the above, main purpose of the present invention provides the method for the citalopram shown in a kind of improved preparation formula III, avoids generating impurity.
Another object of the present invention provides a kind of improved method for preparing citalopram, has high yield (90%) and high purity (99%).
A further object of the invention provides the method for the citalopram shown in a kind of improved preparation formula III, simple, economic and protection environment.
Another object of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates are to the citalopram shown in the preparation formula III of great use.
Another purpose of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates are to the citalopram shown in the preparation formula III of great use.This method can be avoided introducing 3-dimethylamino-propyl side chain in the last stage of preparation citalopram.
A further object of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates are to preparing the citalopram shown in the formula III of great use, and it has adopted a kind of simple crystallization technique.
Further purpose of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates to the citalopram of preparation shown in the formula III of great use, its costliness and dangerous lithium aluminum hydride replaces with simple sodium borohydride, and do not comprise extra step.
Another object of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates to the citalopram of preparation shown in the formula III of great use, acid catalyst of cyclisation step replaced or reduces its consumption during it was synthetic.
Another purpose of the present invention provides a kind of improved preparation formula I ﹠amp; The method of the intermediate shown in the II, these two intermediates are to preparing the citalopram shown in the formula III of great use, and it does not relate to extra step and has simplified technology, and avoids using in a large number solvent (ethanol).
The present invention comes from our discovery, just, if the 3-dimethylamino-propyl side chain that exists in the citalopram was introduced in the last stage, then is difficult to remove with traditional method the impurity of decorrelation.Also have,, then be easy to obtain the acceptable citalopram of pharmacy quality if when one or more separable intermediates form, adopt simple crystallization technique.In view of the above, the invention provides the method for the citalopram shown in a kind of improved preparation formula III,
Comprise:
(i) by in the presence of protonic solvent, coming the compound of preparation formula VIII with inseparable magnesium salts of the benzophenone derivative shown in the sodium borohydride reduction formula V.
(ii) formula VIII compound that will be obtained by step (i) and acid catalyst react in aprotic solvent and obtain the compound shown in the formula I.
(iii) will in polar solvent, react, separate the cyano compound that obtains, obtain formula II compound with polar solvent and/or alcoholic solvent recrystallization by formula I compound and the inferior ketone of cyaniding (I) that step (ii) obtains.
(iii) the formula II compound that obtains is reacted with traditional method and obtain the citalopram shown in the formula III.
The compound of formula II is converted into the compound shown in the formula III can uses chlorination N then in polar solvent such as DMSO, N-dimethylamino-propane cancellation ion and obtain the citalopram shown in the formula III by formula II compound and highly basic such as NaH, t-BuOK are reacted.
According to characteristics of the present invention, a kind of method of improved preparation formula VIII compound is provided, this compound is to the citalopram shown in the preparation formula III of great use.
Comprise:
(i) come preparation formula VIII compound by inseparable magnesium salts in the presence of protonic solvent with the benzophenone derivates shown in the sodium borohydride reduction formula V.
The above-mentioned method for preparing the formula III compound has become the application's division, and promptly our application number is the theme of the common pending application application of----.
According to another embodiment of the present invention, the method for the intermediate shown in a kind of improved preparation formula II is provided, this intermediate is to the preparation citalopram of great use.Comprise:
(i) come preparation formula VIII compound by inseparable magnesium salts in the presence of protonic solvent with the benzophenone derivates shown in the sodium borohydride reduction formula V.
(ii) formula VIII compound that will be obtained by step (i) and acid catalyst react in aprotic solvent and obtain the compound shown in the formula I.
(iii) will in polar solvent, react, separate the cyano compound that obtains, obtain formula II compound with polar solvent and/or alcoholic solvent recrystallization by formula I compound and the inferior ketone of cyaniding that step (ii) obtains.
Present method has become the application's scheme, and promptly our application number is the theme of the common pending application application of----.
According to another embodiment of the present invention, the method for the intermediate shown in a kind of improved preparation formula I is provided, this intermediate is to the preparation citalopram of great use.
Comprise:
(i) come preparation formula VIII compound by inseparable magnesium salts in the presence of protonic solvent with the benzophenone derivates shown in the sodium borohydride reduction formula V.
(ii) formula VIII compound that will be obtained by step (i) and acid catalyst react in aprotic solvent and obtain the compound shown in the formula I.
The method of above-mentioned preparation I compound has become the application's division, and promptly our application number is the theme of the common pending application application of----.
The reduction of step (i) is carried out in for-20-25 ℃ scope in temperature, and preferred temperature range is 0-10 ℃, and the protonic solvent of step (i) can be selected from MeOH, EtOH, IPA, t-BuOH etc.
In another preferred embodiment of the present invention, non-polar solvent such as benzene,toluene,xylene etc. can be used for step (ii), can use catalyzer such as p-TsOH, H
2SO
4, Phenylsulfonic acid etc.
The used crystallization method of separate type II compound comprises dissolving crude product with formula II compound in single solvent such as methyl alcohol, ethanol or Virahol or mixed solvent such as MeOH, IPA/DMF, MeOH/DMF etc., and the blended ratio is 5-6: 1-3, preferred 3-4: 1-2.
Separating the formula II intermediate that obtains with method of the present invention has very high purity (99%, detect with HPLC), and fusing point is 96-97 ℃.Further conclusive evidence to this intermediate quality can be by being converted into desired citalopram hydrobromate with known method (US patent No.4,136,193) with this intermediate, without any need for recrystallization process.What is interesting is that very formula II intermediate has good crystallographic property, all impurity are all stayed in the crystallization medium.
This simplification makes that key intermediate is that the preparation of formula II compound is simple, is easy to adopt suitable method to carry out commercially producing of any scale.And, without any need for the multiple recrystallization technology, just can prepare the citalopram hydrobromate of wanting.
The invention has the advantages that not to need separate type I intermediate to come preparation formula II compound, and this has improved the yield of formula II compound.The result can further increase the yield of citalopram when this method is applied to prepare citalopram.
Embodiment given below describes the present invention in detail, and these embodiment only are used for illustrative purposes, therefore should not be understood that to have limited the scope of further being illustrated by following embodiment of the present invention.
Embodiment 1
The preparation of citalopram
A) preparation of the 4-bromo-of formula VIII (2-methylol)-phenyl-(4 '-fluorophenyl) methyl alcohol is at-10-0 ℃; under the nitrogen protection, will dropwise add by the grignard solution that 90g4-bromofluorobenzene and 13g magnesium chips make in 450ml THF in THF (600ml) suspensoid of 5-bromo-2-benzo [C] furanone (100g).Drip to finish, with reaction mixture restir 3 hours under same temperature, and handle with the soup compound of sodium borohydride (25g) in 300mlIPA, the maintenance reacting liquid temperature is lower than 10 ℃.10 ℃ of insulations after 1 hour, with stopped reaction in the reaction solution impouring dilute hydrochloric acid (in the 220ml concentrated hydrochloric acid add 1750ml water).Reactant was stirred 30 minutes layering.Water layer with toluene 3 * 100ml extraction, is washed the organic layer that merges with saturated sodium-chloride water solution (300ml), used dried over sodium sulfate.Steam in 60 ℃ of following vacuum and to desolventize and obtain the crude product (200g) of formula VIII compound.This compound is adapted at the next stage use of present method.
B) with 1-(4-the fluorophenyl)-5-bromine phthalane of tosic acid as Preparation of Catalyst formula I
The thick oil (200g) of the formula VIII compound that is obtained in a) by above-mentioned steps is dissolved in the 1000ml toluene.In this solution, add the 10g tosic acid, be heated to backflow.Remove the water that generates in the reaction process with Dean-Stark equipment.After the water generation finishes, reactant is chilled to room temperature and adds 1000ml water.Stir after 30 minutes, tell organic layer, water layer extracts with 3 * 100ml toluene, and the organic layer of merging is washed with the aqueous sodium carbonate of 2 * 250m15%.At last organic layer is washed with saturated nacl aqueous solution.Steam the crude product (150g) that removes toluene and obtain buttery formula I compound in 60 ℃ of following vacuum.
C) 1-of preparation formula II (4-fluorophenyl)-5-cyano group phthalan
In the DMF (360ml) of the formula I compound (150g) that obtains by step (b) solution, add freshly prepd cuprous cyanide (76g).The suspension that obtains slowly is heated to backflow, and keeps backflow 4-5 hour.After reactant was chilled to 40-50 ℃, (200ml 10%w/v), and stirred 30 minutes to add ammoniacal liquor.After filtering insoluble salt, layering.With 200ml weak ammonia (10% solution) washing organic layer.Water layer with 100ml toluene extraction merging.The combining methylbenzene layer desolventizes 50-60 ℃ of vacuum steaming, obtains the cyano compound crude product (120g) of semi-solid formula II.
D) with recrystallization technology purifying 1-(4-fluorophenyl)-5-cyano group phthalan
(i) carry out recrystallization from IPA
The crude product (50g) of the formula II compound that will be obtained by step (C) is heated to 60-70 ℃ and is dissolved among the 200mlIPA, and uses the 5g activated carbon treatment.After the filtration, be cooled to 20-25 ℃, kept this temperature 8-12 hour.Cross filter solid, obtain faint yellow crystallization (35g) with the 20-25mlIPA washing, m.p.96-97 ℃, HPLC check purity is 98%.
E) 1-(3-dimethylamino-propyl)-1-(4-the fluorophenyl)-5-cyano group phthalan of preparation formula III
Under 20-25 ℃ of nitrogen protection, in DMSO (1000ml), add the sodium hydride in 22g 50% mineral oil, and slowly be heated to 60-65 ℃, thereby make the DMSO solution of dimsyl sodium.At 20-25 ℃ of DMSO (200ml) solution that in 2-3 hour, slowly in this solution, adds 1-(4-fluorophenyl)-5-cyano group phthalan (100g).Keep reaction after 15-20 minute, toluene (120ml) solution to wherein slowly adding chlorination 3-dimethylamino-propane (56g) keeps temperature of reaction at 25-30 ℃ simultaneously.Reinforced finishing remained on this temperature following 30 minutes with reaction mixture, added 50ml methyl alcohol and made it to decompose.In reaction mixture impouring 3000ml water, with the extraction of 1000ml toluene.Water layer is again with the extraction of 500ml toluene.The toluene layer that merges washes (500ml) with water, uses the acetic acid aqueous solution of 2 * 1000ml 20% to wash then.The acetate water layer that merges is with ammoniacal liquor (25%) pH7-7.5 that neutralizes.After regulating pH, add the 500ml isopropyl ether and stirred 15 minutes.After isolating the isopropyl ether layer, water layer extracts with 2 * 300ml isopropyl ether.The isopropyl ether layer that merges is handled and is filtered with charcoal (10g).Filtrate obtains the compound of formula III 45 ℃ of following evaporated in vacuo, is faint yellow solid (120g).M.p.95 ℃, HPLC check purity is 99%.
Embodiment 2
The preparation of citalopram
A) preparation of the 4-bromo-of formula VIII (2-methylol)-phenyl-(4 '-fluorophenyl) methyl alcohol is at-10-0 ℃; under the nitrogen protection, will dropwise add by the grignard solution that 90g4-bromofluorobenzene and 13g magnesium chips make in 450ml THF in THF (600ml) suspensoid of 5-bromo-2-benzo [C] furanone (100g).Drip to finish, with reaction mixture restir 3 hours under same temperature, and handle with the soup compound of sodium borohydride (25g) in 300ml IPA, the maintenance reacting liquid temperature is lower than 0 ℃.10 ℃ of insulations after 1 hour, with stopped reaction in the reaction solution impouring dilute hydrochloric acid (in the 220ml concentrated hydrochloric acid add 1750ml water).Reactant was stirred 30 minutes layering.Water layer with toluene 3 * 100ml extraction, is washed the organic layer that merges with saturated sodium-chloride water solution (300ml), used dried over sodium sulfate.Steam in 60 ℃ of following vacuum and to desolventize and obtain the crude product (200g) of formula VIII compound.This compound is adapted at the next stage use of present method.
B) with 1-(4-the fluorophenyl)-5-bromine phthalane of Phenylsulfonic acid as Preparation of Catalyst formula I
The crude product oil (200g) of the formula VIII compound that is obtained in a) by above-mentioned steps is dissolved in the 1000ml toluene.In this solution, add the 10g Phenylsulfonic acid, be heated to backflow.Remove the water that generates in the reaction process with Dean-Stark equipment.After the water generation finishes, reactant is chilled to room temperature and adds 1000ml water.Stir after 30 minutes, tell organic layer, water layer extracts with 3 * 100ml toluene.The organic layer that merges is washed with the aqueous sodium carbonate of 2 * 250ml 5%, at last organic layer is washed with saturated nacl aqueous solution.Steam the crude product (150g) that removes toluene and obtain buttery formula I compound in 60 ℃ of following vacuum.
C) 1-of preparation formula II (4-fluorophenyl)-5-cyano group phthalan
In the DMAc (360ml) of the formula I compound (150g) that obtains by step (b) solution, add freshly prepd cuprous cyanide (76g).The suspension that obtains slowly is heated to 150-160 ℃, and kept temperature 4-5 hour.After reactant was chilled to 40-50 ℃, (200ml 10%w/v), and stirred 30 minutes to add ammoniacal liquor.After filtering insoluble salt, layering.With 200ml weak ammonia (10% solution) washing organic layer.Water layer with 100ml toluene extraction merging.The combining methylbenzene layer desolventizes 50-60 ℃ of vacuum steaming, obtains the cyano compound crude product (120g) of semi-solid formula II.
D) with recrystallization technology purifying 1-(4-fluorophenyl)-5-cyano group phthalan
(i) carry out recrystallization from methyl alcohol
The crude product (50g) of the formula II compound that will be obtained by step (C) is dissolved in the methyl alcohol that 150ml refluxing, and adds the 5g coke.Filter out carbon and be cooled to 20-25 ℃, kept this temperature 8-12 hour.Cross filter solid, obtain the 25g white crystals with 25ml methanol wash filter cake, m.p.97-98 ℃, HPLC check purity is 99%.
E) 1-(3-dimethylamino-propyl)-1-(4-the fluorophenyl)-5-cyano group phthalan of preparation formula III
20-25 ℃ and stir under, in 2-3 hour, slowly add the solution of the DMSO (200ml) of 1-(4-fluorophenyl)-5-cyano group phthalan (100g) in the suspension in 22g sodium hydride (in paraffin oil, containing 50-55%) 1000ml DMSO.Keep reaction after 15-20 minute,, keep temperature of reaction at 25-30 ℃ to toluene (120ml) solution that wherein slowly adds chlorination 3-dimethylamino-propane (56g).Reinforced finishing with reaction mixture insulation reaction 30 minutes, adds 50ml methyl alcohol and makes it to decompose.In reaction mixture impouring 3000ml water, with the extraction of 1000ml toluene.Water layer is again with the extraction of 500ml toluene.The toluene layer that merges washes (500ml) with water, uses the acetic acid aqueous solution of 2 * 1000ml 20% to wash then.The acetate water layer that merges is with ammoniacal liquor (25%) pH7-7.5 that neutralizes.After regulating pH, adding 500ml isopropyl ether also stirred 15 minutes.Isolate the isopropyl ether layer, water layer extracts with 2 * 300ml isopropyl ether.The isopropyl ether layer that merges is handled and is filtered with charcoal (10g).Filtrate obtains the formula III compound 45 ℃ of following evaporated in vacuo, is faint yellow solid (120g).M.p.95 ℃, HPLC check purity is 99%.
Embodiment 3
The preparation of citalopram
A) preparation of the 4-bromo-of formula VIII (2-methylol)-phenyl-(4 '-fluorophenyl) methyl alcohol
At-10-0 ℃, under the nitrogen protection, will dropwise add by the grignard solution that 90g4-bromofluorobenzene and 13g magnesium chips make in 450ml THF in THF (600ml) suspension of 5-bromo-2-benzo [C] furanone (100g).Drip to finish, with reaction mixture restir 3 hours under same temperature, and handle with the soup compound of sodium borohydride (25g) in 200ml ethanol, the maintenance reacting liquid temperature is lower than 0 ℃.10 ℃ of insulations after 1 hour, with stopped reaction in the reaction solution impouring dilute hydrochloric acid (in the 220ml concentrated hydrochloric acid add 1750ml water).Reactant was stirred 30 minutes layering.Water layer with toluene 3 * 100ml extraction, is washed the organic layer that merges with saturated sodium-chloride water solution (300ml), used dried over sodium sulfate.Steam in 60 ℃ of following vacuum and to desolventize and obtain the crude product (200g) of formula VIII compound.This compound is adapted at the next stage use of present method.
B) with 1-(4-the fluorophenyl)-5-bromine phthalane of sulfuric acid as Preparation of Catalyst formula I
Crude product oil (200g) by the formula VIII compound that obtains among the embodiment 3 (a) is dissolved in the 1000ml toluene.In this solution, add the 10g vitriol oil.Reaction mixture is heated to backflow, and removes the water that generates in the reaction process with azeotropic method.After reaction was finished, conventional processing obtained the crude product compound of 150g oily formula II.
C) 1-of preparation formula II (4-fluorophenyl)-5-cyano group phthalan
In pyridine (150ml) solution of the formula I compound (150g) that obtains by step (b), add freshly prepd cuprous cyanide (76g).The suspension that obtains slowly is heated to backflow, and keeps backflow 4-5 hour.After reactant was chilled to 40-50 ℃, (200ml 10%w/v), and stirred 30 minutes to add ammoniacal liquor.After filtering insoluble salt, layering.With 200ml weak ammonia (10% solution) washing organic layer.Water layer with 100ml toluene extraction merging.The combining methylbenzene layer desolventizes 50-60 ℃ of vacuum steaming, obtains the cyano compound crude product (120g) of semi-solid formula II.
D) 1-(4-fluorophenyl)-5-cyano group phthalan of usefulness recrystallization technology purifying formula II
(i) carry out recrystallization from IPA-DMF
The crude product (150g) of the formula II compound that will be obtained by step (C) is dissolved among the 100mlIPA-DMF (80: 20) at 50-60 ℃, and uses the 5g activated carbon treatment.After filtering out gac, filtrate is cooled to 10-15 ℃, keeps this temperature 3-4 hour.Filter out solid, obtain white crystals with the 20mlIPA washing leaching cake, m.p.97-98 ℃, HPLC check purity is 98.5%.
E) 1-(3-dimethylamino-propyl)-1-(4-the fluorophenyl)-5-cyano group phthalan of preparation formula III
Under agitation, at 20-25 ℃ of DMSO (200ml) solution that in the suspension of 59g potassium tert.-butoxide in 1000ml DMSO, in 2-3 hour, slowly adds 1-(4-fluorophenyl)-5-cyano group phthalan (100g).Keep reaction after 15-20 minute,, keep temperature of reaction at 25-30 ℃ to toluene (120ml) solution that wherein slowly adds chlorination 3-dimethylamino-propane (56g).Reinforced finishing with reaction mixture insulation reaction 30 minutes, adds 50ml methyl alcohol and makes it to decompose.In reaction mixture impouring 3000ml water, with the extraction of 1000ml toluene.Water layer is again with the extraction of 500ml toluene.The toluene layer that merges washes (500ml) with water, uses the acetic acid aqueous solution of 2 * 1000ml20% to wash then.The acetate water layer that merges is with ammoniacal liquor (25%) pH7-7.5 that neutralizes.After regulating pH, adding 500ml isopropyl ether also stirred 15 minutes.Separate the isopropyl ether layer, water layer extracts with 2 * 300ml isopropyl ether.The isopropyl ether layer that merges is handled and is filtered with charcoal (10g).Filtrate obtains the compound of formula III 45 ℃ of following evaporated in vacuo, is faint yellow solid (100g).M.p.95 ℃, HPLC check purity is 99%.
Advantage of the present invention:
1. replace lithium aluminium hydride reduction with sodium borohydride, obviously reduced cost and got rid of danger.
2. the simple knot crystal method of the cyano compound of formula II has been avoided corresponding formula I compound High vacuum distillation.
3. obtained final formula III compound with high yield (88%) and high-purity (99%).
4. this method is fit to any commercial size, protection of the environment and economy.
Claims (8)
1. the method for the citalopram of an improved preparation formula III,
Comprise:
(i) by in the presence of protonic solvent, coming the compound of preparation formula VIII with inseparable magnesium salts of the benzophenone derivates shown in the sodium borohydride reduction formula V;
(ii) formula VIII compound that will be obtained by step (i) and acid catalyst react in non-polar solvent and obtain the compound shown in the formula I;
(iii) will in polar solvent, react, separate the cyano compound that obtains, obtain the compound of formula II with polar solvent and/or alcoholic solvent recrystallization by formula I compound and the inferior ketone of cyaniding that step (ii) obtains;
(iv) the formula II compound that obtains is reacted with traditional method and obtain the citalopram shown in the formula III.
2. the method in the claim 1 is wherein used protonic solvent such as MeOH, EtOH, IPA, t-BuOH in step (i), preferably uses methyl alcohol.
3. the method in the claim 1 and 2 is wherein used non-polar solvent such as benzene,toluene,xylene, hexanaphthene in (ii) in step, preferably uses toluene.
4. the method among the claim 1-3 is wherein used catalyzer such as Phenylsulfonic acid, tosic acid, sulfuric acid in (iii) in step, preferably uses tosic acid.
5. the method among the claim 1-4, wherein step (ii) in used recrystallization solvent be selected from methyl alcohol, IPA, ethanol, be with or without DMF, or its mixture.
6. the method in the claim 5, wherein recrystallization solvent is the mixture of IPA and DMF.
7. the method in the claim 6, the proportional range of wherein used IPA and DMF is from 5-6: 1-3, and preferable range is 3-4: 1-2.
8. improving one's methods of a citalopram for preparing formula III carried out with reference to the described method of embodiment 1-3 basically.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN157/MAS/2001 | 2001-02-22 | ||
| IN157CH2001 | 2001-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1492861A true CN1492861A (en) | 2004-04-28 |
Family
ID=34074047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028054199A Pending CN1492861A (en) | 2001-02-22 | 2002-02-11 | Process for preparation of citalopram |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20040133017A1 (en) |
| EP (1) | EP1368330A1 (en) |
| JP (1) | JP2004529883A (en) |
| CN (1) | CN1492861A (en) |
| CA (1) | CA2438650A1 (en) |
| NO (1) | NO20033743L (en) |
| WO (1) | WO2002066453A1 (en) |
| ZA (1) | ZA200306063B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435838B2 (en) | 2003-12-19 | 2008-10-14 | Hangzhou Minsheng Pharmaceutical Co. Ltd. | Crystalline citalopram diol intermediate alkali |
| CN103483300A (en) * | 2013-09-25 | 2014-01-01 | 东南大学 | Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004016602A1 (en) * | 2002-08-14 | 2004-02-26 | Natco Pharma Limited | Process for the preparation of high purity citalopram and its pharmaceutically acceptable salts |
| GB2385051B (en) * | 2002-08-29 | 2003-12-24 | Max India Ltd | Improved process for the preparation of 5-substituted-1 (4-fluorophenyl)-1,3-dihydro isobenzofurans |
| AU2003263155A1 (en) * | 2002-09-20 | 2004-04-08 | H. Lundbeck A/S | Method for manufacture of dihydroisobenzofuran derivatives |
| AU2003238676A1 (en) * | 2003-04-21 | 2004-11-19 | Podile Khadgapathi | An improved process for the preparation of citalopram hydrobromide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1526331A (en) * | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
| US5770180A (en) * | 1992-08-24 | 1998-06-23 | Organix, Inc. | Bridge-substituted tropanes for methods of imaging and therapy |
| MXPA04008803A (en) * | 2002-03-13 | 2004-11-26 | Schering Corp | Nk1 antagonists. |
-
2002
- 2002-02-11 CA CA002438650A patent/CA2438650A1/en not_active Abandoned
- 2002-02-11 CN CNA028054199A patent/CN1492861A/en active Pending
- 2002-02-11 WO PCT/IN2002/000023 patent/WO2002066453A1/en not_active Application Discontinuation
- 2002-02-11 US US10/468,973 patent/US20040133017A1/en not_active Abandoned
- 2002-02-11 JP JP2002565969A patent/JP2004529883A/en not_active Withdrawn
- 2002-02-11 EP EP02705037A patent/EP1368330A1/en not_active Withdrawn
-
2003
- 2003-08-06 ZA ZA200306063A patent/ZA200306063B/en unknown
- 2003-08-22 NO NO20033743A patent/NO20033743L/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435838B2 (en) | 2003-12-19 | 2008-10-14 | Hangzhou Minsheng Pharmaceutical Co. Ltd. | Crystalline citalopram diol intermediate alkali |
| CN103483300A (en) * | 2013-09-25 | 2014-01-01 | 东南大学 | Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone |
| CN103483300B (en) * | 2013-09-25 | 2015-05-06 | 东南大学 | Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20033743L (en) | 2003-10-16 |
| EP1368330A1 (en) | 2003-12-10 |
| JP2004529883A (en) | 2004-09-30 |
| ZA200306063B (en) | 2004-07-16 |
| US20040133017A1 (en) | 2004-07-08 |
| NO20033743D0 (en) | 2003-08-22 |
| WO2002066453A1 (en) | 2002-08-29 |
| CA2438650A1 (en) | 2002-08-29 |
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